MDA Conference Brings Together Researchers, Clinicians, Industry

An MDA-sponsored meeting explored progress in five key therapeutic strategies under development for neuromuscular diseases

Cutting-edge strategies to treat neuromuscular diseases were the focus of the three-day conference. At a break, conference participants posed for a photo tied to MDA's new "Make a Muscle, Make a Difference" fundraising campaign.

Article Highlights:

Some 300 researchers, clinicians, representatives from biotech and pharmaceutical industries, and students specializing in neuromuscular disease gathered in Las Vegas March 13-16, 2011, for a conference on five current leading therapeutic strategies.

Strategies using oligonucleotides to block genetic instructions, stem cells to study or treat disease, and small molecules, proteins and genes as therapeutic agents were presented.

Moving therapeutic strategies from the laboratory to clinical trials and ultimately to the market as treatments was the theme of the MDA National Scientific Conference held March 13-16, 2011, in Las Vegas.

Some 300 people attended the conference, the first in a planned series of such MDA-sponsored meetings that will emphasize new research and current medical care. The majority of presenters and many of the audience members were current or former MDA research grantees or physicians at MDA-supported clinics.

The conference explored several leading therapeutic strategies, most of which have application to a number of neuromuscular disorders in MDA’s program.

It brought together senior researchers and physicians, representatives from the biotechnology and pharmaceutical industries, and students beginning their research and clinical careers in neuromuscular disease. The interchange of information from a variety of perspectives will be valuable in further developing these strategies and moving them toward clinical trials.

Steve Wilton is a longtime MDA research grantee at the University of Western Australia, where he's developing antisense oligonucleotides to restore dystrophin production in Duchenne muscular dystrophy. He gave the keynote speech at the oligonucleotide session of the conferenc

"This meeting was the first of its kind — a meeting entirely dedicated to therapeutic development for a broad range of neuromuscular diseases," said MDA Vice President-Research Sanjay Bidichandani.

The strategies presented at the conference included oligonucleotides, stem cells, small molecules, protein therapy and gene therapy. Below are some highlights of the meeting.

Antisense oligonucleotides

Antisense oligonucleotides are short strands of chemicals called nucleotides that can be used to target specific genetic instructions and change the way cells interpret these instructions.

In FSHD, the apparently toxic DUX4 protein instructions potentially can be blocked by oligonucleotides. In MMD1, the goal is to block or destroy the genetic instructions for the DMPK protein. Laboratory experiments in these diseases look promising. In MMD2, the target will be to interfere with the genetic instructions for the ZNF9 protein. These experiments are not yet under way.

In ALS, the goal of oligonucleotides is to block the genetic instructions for toxic SOD1 protein. A clinical trial to test this approach is under way for patients with SOD1-mediated familial ALS.

In Duchenne muscular dystrophy (DMD), oligonucleotides can be used to mask certain segments of genetic instructions for the dystrophin gene so that a functional dystrophin protein can be made. This strategy — also known as “exon skipping” because it causes the cell to skip certain regions (exons) of the genetic instructions for the dystrophin gene — is being tested in clinical trials in boys with DMD. Animal studies have been extremely encouraging.

Alessandra Belayew has received MDA support for her research on facioscapulohumeral muscular dystrophy at the University of Mons in Belgium. At the conference, she presented her recent work on the use of antisense strategies for FSHD.

In the recessively inherited disease spinal muscular atrophy (SMA), the goal is to change the way the cell reads genetic instructions for the SMN protein so that a functional SMN protein can be produced. Experiments are under way to cause inclusion of a section of the SMN gene called exon 7. In this case, oligonucleotides will be used to cause “exon inclusion,” rather than exon skipping.

Stem cells

Stem cells are either precursors to a specific cell type (such as muscle or nerve cells) or they are cells that have the potential to develop into multiple cell types. Studying stem cells can increase understanding of how nerve and muscle tissues develop normally and in neuromuscular diseases. Some types of stem cells are in development as cell transplantation therapies.

In FSHD, patient-derived cells that have been reprogrammed to become stem cells (“induced pluripotent stem cells”) are being used to study how the disease develops and to test potential therapies in a “disease in a dish.”

In ALS, a clinical trial of neural precursor cells derived from a fetal spinal cord is under way. These cells are being injected directly into patients’ spinal cords.

In a different clinical trial, transplantation into the spinal cord of “mesenchymal” stem cells, derived from the bone marrow, has shown the approach to be feasible and safe.

Another approach to treating ALS may be repairing blood vessels in structures known as the “blood-brain barrier” and “blood-spinal cord barrier,” which appear to be disrupted and abnormally permeable in ALS. It may be possible to coax stem cells into repairing these barriers, and doing so may protect nerve cells.

In DMD, various types of muscle stem cells are being considered to replace or repair degenerating muscle fibers. A clinical trial is under way in Italy to test the safety and possible benefits of a type of stem cell known as the “mesoangioblast,” which is associated with blood vessels but which can develop into muscle tissue.

Small molecules

Many drugs are “small molecules” that are considerably smaller than proteins and many times smaller than cells. They are generally easier to deliver to targeted tissues than proteins or cells and are less likely to elicit an unwanted immune response.

A small molecule known as a histone deacetylase (HDAC) inhibitor is in development as a potential treatment for Friedreich’s ataxia (FA). The HDAC inhibitor targets the genetic instructions for the frataxin protein, coaxing the cell to make functional frataxin protein molecules despite the presence of a mutation in the frataxin gene. Frataxin protein deficiency is the underlying cause of FA.

Also being studied in FA are small molecules known as antioxidants, which can counteract a type of cell damage known as oxidative stress.

In SMA, a small molecule under development is designed to change the way cells interpret the genetic instructions for SMN, coaxing production of this needed protein.

In DMD and the related Becker muscular dystrophy (BMD), a small molecule known as sildenafil (which already is on the market as Viagra) is in development as a treatment to improve skeletal and cardiac muscle function. A similar molecule, tadalafil (on the market as Cialis) also is being explored. These drugs appear to increase blood flow to exercising muscle and also have cardiac effects that may be beneficial in DMD and BMD. Clinical trials in these diseases are under way.

An emerging strategy in DMD, and possibly in BMD, are small molecules that combat inflammation. Corticosteroids like prednisone and deflazacort are widely used in DMD, but they have harmful side effects, such as weight gain and bone loss, if given for long periods of time at relatively high doses. Attempts are now being made to develop potent anti-inflammatory drugs that don’t have the side effects of corticosteroids. A compound known as VBP-15 is likely to be carried forward into clinical trials.

In ALS, a new and promising experimental therapeutic strategy is the use of small molecules that activate neuroprotective pathways. Small molecules that cause proliferation of glial cells, which provide crucial metabolic support to nerve cells, is one such approach. Targeting a chemical pathway known as MCT1 also looks promising as an approach to protecting motor neurons, the nerve cells that die in this disease.

Another strategy for ALS is targeting the cell death pathway in motor neurons. A small molecule called necrostatin 1 appears to be a potent inhibitor of the BNIP3 cell death pathway and is being explored as an ALS therapy.

A similar strategy is being investigated for the treatment of SMA, in which a degenerative pathway known as JNK is being targeted. Inhibitors of JNK signaling could become SMA treatments.

In centronuclear myopathies (CNMs), including myotubular myopathy (MTM), evidence is accumulating that there is an unexpected defect at the neuromuscular junction, the place where nerve and muscle fibers meet and where nerve fibers send activating signals to muscle via acetycholine.

Some individuals with CNMs have responded to pyridostigmine (brand name Mestinon), which has been used for many years to treat neuromuscular transmission defects such as myasthenia gravis (MG) and other forms of myasthenia. Although not a cure, this small-molecule drug appears to modestly increase function and may improve quality of life in some CNM/MTM patients.

Charles Thornton (right) has received MDA support for research on several neuromuscular diseases at the University of Rochester (N.Y.), where he also directs the MDA/ALS Center and co-directs the MDA neuromuscular disease clinic. Thornton was a co-chairman of the conference, as was Robert Mattaliano (left), group vice president of protein research and development at Genzyme.

Protein therapy

Genes are the instructions that cells use to manufacture proteins, which then carry out the majority of cellular functions. Proteins have great potential as treatments for neuromuscular diseases, such as compensating for proteins that are missing or interfering with proteins that are toxic. Their development as therapies generally poses more challenges than development of small molecules, but there have been remarkable success stories in this field.

Shining examples of this are the development and approval by the U.S. Food and Drug Administration (and regulatory agencies in other countries) of the protein-based therapies Myozyme and Lumizyme to treat Pompe disease (acid maltase deficiency or AMD).Myozyme and Lumizyme are replacements for the missing or deficient acid maltase protein.

In DMD, and potentially in other muscle diseases, inhibition of the naturally occurring protein myostatin, which limits muscle growth and regeneration, is an extremely promising strategy. The experimental drug ACE-031, which is a laboratory-developed protein that interferes with the myostatin protein, is now being tested in a clinical trial in boys with DMD.

Also in DMD, the protein biglycan appears to attract the beneficial protein utrophin to the muscle-fiber membrane in animal experiments. It may have therapeutic potential in this disease.

In the form of congenital muscular dystrophy (CMD) that results from the loss of the laminin alpha 2 protein, administering a protein called laminin 111 has shown benefit in animal models.

Gene therapy

Gene therapy, or gene transfer, refers to delivering genes as therapeutic agents. Since genes serve as the instructions for proteins, they can lead to production of proteins that are directly or indirectly therapeutic in neuromuscular diseases.

Gene therapy faces many technical challenges, as well as a high bar set by regulatory agencies such as the Food and Drug Administration. However, transferred genes could provide long-lasting benefit compared to protein therapy or other therapies, since cells would probably continue producing protein from these genes for some time.

The key challenges for gene therapy are delivering the genes to the targeted tissue while avoiding nontargeted tissues; and avoiding an unwanted immune response to the proteins made from the new genes or to the delivery vehicles in which the new genes are delivered. Since the most effective delivery vehicles to date are derived from viruses, the immune system is predisposed to attack them.

Gene therapy for DMD has been in development for several years. A recent clinical trial involving intramuscular injection of a miniaturized dystrophin gene inside an adeno-associated viral (AAV) shell uncovered unexpected types of immune responses that are incompletely understood and are being explored. The therapy appeared to be safe, at least at the low doses used, but the immune responses appear to have interfered with prolonged production of the dystrophin protein.

In a dog model of DMD, a brief course of immunosuppression allowed long-term and robust dystrophin production in skeletal muscles after gene transfer. Immunosuppressant drug treatment may be necessary in conjunction with dystrophin gene transfer in humans.

Another type of gene therapy being considered in DMD involves transferring genes for the protein claudin 5 to treat cardiac aspects of these diseases. This approach has shown great promise in treating cardiomyopathy (heart-muscle damage) in a mouse model of severe DMD.

Blocking the myostatin protein via a protein called follistatin is a strategy that has potential for treating DMD and likely many other neuromuscular diseases. Mice with a DMD-like disease that received genes for the follistatin protein showed an overall increase in body mass and weight of individual muscles. Monkeys that received follistatin gene transfer had stronger, as well as larger, muscles.

In a mouse model of FSHD, researchers are studying the possible use of DNA that codes for oligonucleotides that block toxic proteins. This strategy could lead to long-term production of protein-blocking agents.

Delivery of genes to the central nervous system has been complicated by the existence of the blood-brain and blood-spinal cord barriers. A new delivery vehicle, based on the shell of a type 9 adeno-associated virus (AAV9), has overcome this barrier in laboratory models of SMA. SMN-deficient mice with an SMA-like disease have shown remarkable benefit from the delivery of SMN genes in AAV9 shells.

The strategy is being considered for clinical trials in patients with SMA. A caveat is that SMN may need to be given very early in life for maximum benefit.

Delivery of follistatin genes to treat SMA is also being considered. SMA is a disease of motor neurons, but like ALS, the end result is muscle weakness and atrophy, as muscles lose their usual activating signals from the nervous system. In a mouse model of SMA, muscle size and force generation increased after follistatin gene therapy.